Safety Study of Orally Administered Curcuminoids in Adult Subjects With Cystic Fibrosis (SEER)

• Safety and tolerability of 14 days of treatment with orally administered Curcuminoids as assessed by:
• - adverse events
• - abnormal changes in laboratory parameters
• - changes in spirometry.

• - Pharmocokinetics of repeated doses of orally administered Curcuminoids
• - Change in nasal potential difference measurements from Screening (Visit 1) to Day 8 (Visit 3), Screening to Day 15 (Visit 4), and Day 8 to Day 15. Specifically:
• * The change in low chloride plus isoproterenol response
• * The change in basal PD
• * The change in amiloride response
• - Change in sweat chloride measurements from Baseline (at Visit 1, or at Visit 2 prior to dosing, or any day between Visits 1 and 2) to Day 15

The purpose of this study is to assess the safety of advancing doses of curcuminoids administered orally for fourteen consecutive days in adult subjects with cystic fibrosis (CF) who are homozygous for ΔF508 CFTR.

The drug substance being studied is curcumin. Curcumin (diferuloylmethane) is a major constituent in the spice turmeric, which is used as a food worldwide.

The pharmacologic rationale for studying curcumin for the treatment of cystic fibrosis is the potential for curcumin to help correct a deficiency of the cystic fibrosis transmembrane regulator (CFTR) protein. Cystic fibrosis results from a mutation of the CFTR gene, which produces abnormal CFTR protein that does properly transport chloride ion and water in the lung leading to abnormal mucus production. Curcumin is a potent inhibitor of the endoplasmic reticulum (ER) Ca2+ pump, and lowers ER calcium concentration. This may allow abnormal CFTR protein to function properly as a chloride channel and correct the cystic fibrosis defect. If this is successful, this effect could be measured as a decrease in the nasal potential difference (NPD) and sweat chloride in cystic fibrosis patients.

The primary objective of this study is to assess the safety of advancing doses of curcuminoids administered orally for fourteen consecutive days in adult subjects with cystic fibrosis (CF) who are homozygous for ΔF508 CFTR. The secondary objectives are to obtain pharmacokinetic data for oral curcumoniods in CF subjects and to assess the effectiveness of curcuminoids to alter nasal potential difference (NPD) and seat chloride concentrations.

Inclusion Criteria:

• Male or female 18 - 40 years of age.
• Documented history of being homozygous for ΔF508 CFTR genotype.
• Able to perform spirometry maneuvers, and have a forced expiratory volume at 1 second (FEV1) greater than or equal to 30% of predicted normal for age, gender, and height (Knudson standards) at screening.
• Oxygen saturation (as measured by pulse oximetry) > 90% on room air at screening.
• Clinically stable with no evidence of acute upper or lower respiratory tract infection.
• Non-smoker for at least 6 months prior to screening.
• Able to understand and sign a written informed consent and comply with the requirements of the study.

Exclusion Criteria:

• Diagnosis of acute pulmonary exacerbation (PE) requiring antibiotic intervention within 4 weeks prior to screening.
• Patient reported history of viral upper respiratory tract infection within 2 weeks prior to screening.
• History of major complications of lung disease (including recent massive hemoptysis or pneumothorax) within two months prior to screening Visit.
• Acute nosebleeds within 14 days prior to screening.
• Nasal surgery within 4 weeks prior to screening.
• Begun use of nasal antibiotics, nasal steroids, nasal cromolyn, nasal atrovent, nasal phenylephrine, or oxymetazoline within 14 days prior to screening.
• Chest x-ray at screening or within 3 months of screening with abnormalities suggesting clinically significant active pulmonary disease other than cystic fibrosis, and/or new CF-specific changes including atelectasis, small pneumothoraces, or pneumonia.
• EKG at screening which shows clinically significant abnormality including prolonged QTc, bundle branch block, rhythm other than sinus, evidence of ischemic heart disease.

• Seer Pharmaceuticals
• CF Therapeutics Development Network Coordinating Center
• Cystic Fibrosis Foundation Therapeutics